European Heart Journal Advance Access originally published online on August 30, 2009
European Heart Journal 2009 30(20):2431-2432; doi:10.1093/eurheartj/ehp365
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The quest for a ‘better mousetrap’
Heart and Vascular Program, Baystate Medical Center, Springfield, MA 01199, USA
* Corresponding author. Tel: +1 413 794 3015, Fax: +1 413 794 9294, Email: aaron.kugelmassmd{at}bhs.org
This commentary refers to ‘Randomized, non-inferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial’
, by R.A. Byrne et al., on page 2441
Percutaneous coronary intervention has been limited by the diminution of acute luminal gain over time. The limitations of conventional balloon angioplasty spawned a variety of different devices, all with the hope of identifying a device that would durably preserve acute luminal gains with an excellent safety profile. To date, the evolutionary victor in this search appears to be the drug-eluting stent. Commercially available drug-eluting stents have demonstrated durable long-term results.1 Despite this, questions concerning both the long-term efficacy and safety of drug-eluting stents have persisted, be it catch up restenosis or late stent thrombosis.2 Thus, the quest for the ideal device continues.
Byrne and colleagues report a randomized trial of three limus agent-eluting stents with biodegradable or permanent polymer coating (the ISAR-TEST-4 Study).3 This study of >2600 patients is the largest randomized trial of a biodegradable polymer-based drug-eluting stent to date, and compares a novel biodegradable polymer-based, rapamycin-eluting stent with the two leading limus-based drug-eluting stents, sirolimus (Cypher) and everolimus (Xience). As such, it builds on the experience of other major randomized trials, observational studies, and registries utilizing biodegradable polymer-based drug-eluting stents.2,4–6 Combined, this provides an expanding platform by which to study and develop what may potentially prove to be the next iteration of coronary drug-eluting stent technology.
The appeal of a biodegradable polymer drug-eluting stent is readily evident. Drug-eluting stents were developed utilizing antiproliferative agents to inhibit the neoimtimal hyperplasia that results from bare metal stent implantation. Drugs are released relatively quickly (90 days) from current polymers, but the polymers persist indefinitely.7 Pathological studies and observations associate the permanent polymers with smooth muscle cell apoptosis, ongoing inflammation, fibrination, hypersensitivity, and thrombogenicity.2,7,8 This in turn probably contributes to the angiographic and clinical challenges of delayed and incomplete endothelialization, malapposition, late lumen creep, delayed restenosis, and late and very late stent thrombosis. Thus, the permanent polymer contributes to many of the clinical and angiographic challenges for current drug-eluting stents. Put another way, the permanent polymer probably negates some of the benefit of the agent that it serves to bind and elute. A biodegradable polymer that effectively released antiproliferative agents, yet itself was safely degraded and did not leave a biological footprint, would represent a significant iterative development in drug-eluting stent technology.
Despite the novelty of the polymer and stent technology in the ISAR-TEST-4 trial, the study population is comparatively ‘non-idealized’. Reflecting contemporary ‘real world’ practice, it includes acute coronary syndrome, as well as stable angina patients. Likewise, the proportion of patients with diabetes mellitus, prior myocardial infarction, and multivessel coronary artery disease mirror contemporary patient populations. In this study the mean vessel size was 
2.8 mm, >70% of treated lesions were classified as B2 or C, and close to one-third of patients had multiple lesions stented. Thus, the angiographic characteristics of the study lesions reflect contemporary challenges. While the angiographic and clinical success of the index procedure are not reported, the reported 30 day results suggest no significant difference in these metrics between the currently available drug-eluting stents and those of the tested device. This suggests an iterative device that is both deliverable and safe in deployment. However, clarification rather than suggestion of this point is critical in ongoing device development.
At both 30 days and 12 months, the biodegradable polymer stent was significantly non-inferior (P = 0.005) to the available limus stents for a composite endpoint that includes both safety (cardiac death/myocardial infarction) and clinical restenosis [target lesion revascularization (TLR)]. Each of the contributing endpoints appeared similar. A limited subset analysis (age, diabetes, gender, and vessel size) does not identify a group for whom the biodegradable polymer-based device appears to have an acute or intermediate safety issue. Likewise, the 12 month incidence of Academic Research Consortium-defined definite/probable stent thrombosis is similar for the biodegradable polymer stent.10 If anything, there appears to be a non-significant advantage for the novel stent. These findings are encouraging, but beget the question as to what is the appropriate clinical and angiographic surveillance period for biodegradable polymer stents. As is evident from drug-eluting stents, attempts to reduce vascular inflammation can result in temporal shifts in angiographic and clinical sequellae.7,11–14 Despite the theoretical advantages of a biodegradable polymer, this report must be viewed as only an initial encouragement for this technology. New device evolution has brought with it previously undescribed side effects or complications (e.g. bare metal stent in-stent restenosis, drug-eluting stent edge restenosis, delayed restenosis, and late stent thrombosis). It is naïve to believe that a novel technological breakthrough will be free of an as yet to be determined new limitation. The authors suggest that there will be a 2-year follow-up for this cohort. It is critical that study participants be followed long term—5 years or more—in order both to establish safety and efficacy, and to help better define the appropriate surveillance window for these devices.
The angiographic findings of this trial are not included in this report. Such information is critical. The late loss of reported biodegradable polymers and bioabsorbable stents has ranged widely.2,5,15 Is there a significant difference between the novel device reported in this report and the limus stents, both of which are notable for comparatively low late loss? If so, is this biodegradable stent ‘on the cusp’ of a significant difference in restenosis-driven clinical events over a longer duration, or when used in more complex patient sets? Twelve-month angiographic data would be helpful in assessing those possibilities. Likewise, is the new technology prone to its own delayed angiographic sequellae? This could include delayed late loss or lumen creep. As the authors surmise, it is possible that the biodegradation process itself is an inflammatory process and may adversely impact vascular healing. Thus, long-term angiographic follow-up, probably beyond 2 years, will be crucial in the ongoing evaluation of this technology.
This study demonstrates the acute and intermediate term clinical non-inferiority of a novel biodegradable polymer-based drug-eluting stent. The promise of this technology is that it can be applied to create drug-eluting stents that are clinically and angiographically superior to the current permanent polymer stents. This poses a significant challenge. Biodegradable polymer platforms will need to demonstrate ease of deliverability and safe deployment, as measured by equivalent or superior acute angiographic and clinical success. The clinical and angiographic follow-up will need to be lengthy and robust. The outcomes will need to be significantly better, not equivalent to our current stent technology. If, and whether, this will represent reduced late restenosis or stent thrombosis, or perhaps other clinical advantages, remains to be determined. Will biodegradable technology allow for reduced duration of dual antiplatelet therapy?
Will the results of biodegradable polymer stents prove that they are as durable as current drug-eluting stent? This report of the ISAR-TEST-4 trial provides encouraging acute and intermediate support for this quest. Long-term clinical and angiographic data will be essential. This trial, the largest to date, adds to the platform for testing and developing this technology as part of the quest for the ‘better mousetrap’ of coronary devices.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehp352 
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Related articles in EHJ:
- Randomized, non-inferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial
- Robert A. Byrne, Adnan Kastrati, Sebastian Kufner, Steffen Massberg, K. Anette Birkmeier, Karl-Ludwig Laugwitz, Stefanie Schulz, Jürgen Pache, Massimiliano Fusaro, Melchior Seyfarth, Albert Schömig, Julinda Mehilli, and for the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Investigators
EHJ 2009 30: 2441-2449.[Abstract] [FREE Full Text]
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